Identification of Novel, Drug-like Inhibitors of Hsp90

新型 Hsp90 类药物抑制剂的鉴定

• 批准号: 7272121
• 负责人: Martha Kelly
• 金额: $ 23.56万
• 依托单位: LOCUS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7272121
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin; ATP phosphohydrolase; Affinity; Ansamycin Antineoplastic Antibiotic; Binding; Binding Sites; Bioavailable; Biological; Cells; Chemicals; Class; Client; Clinic; Computer Simulation; Cooperative Research and Development Agreement; Crystallography; Development; Disruption; Drug Delivery Systems; Drug Design; Drug Kinetics; Evaluation; FYN gene; Family; Free Energy; GRP94; Geldanamycin Analogue; Genetic; Genetic Transcription; Government; Growth; HSP 90 inhibition; Heat-Shock Proteins 90; In Vitro; Indazoles; Lead; Malignant Neoplasms; Maps; Modeling; Molecular; Molecular Chaperones; Molecular Target; Molecular Weight; Mutate; N-terminal; Numbers; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Principal Investigator; Process; Property; Proteins; Purpose; Pyrazoles; Research; Resistance; Rifabutin; Series; Signal Transduction; Structure; TP53 gene; Technology; Therapeutic; Therapeutic Agents; Toxic effect; Validation; Work; analog; anti-cancer therapeutic; base; cancer cell; cancer therapy; chemotherapeutic agent; commercial application; design; improved; inhibitor/antagonist; innovation; novel; programs; pyrazole; small molecule; steroid hormone receptor

DESCRIPTION (provided by applicant): Despite recent advances in cancer treatment, the identification of novel anti-cancer therapeutic agents remains a pressing need. Heat Shock Protein 90 (Hsp90) is a molecular chaperone which binds to and folds several client proteins including a number of key cancer-relevant targets such as the kinases Bcr-Abl, Raf-1, and SRC family kinases such as SRC, LCK and FYN, mutated p53, ErbB2, and the steroid hormone receptors. Disruption of the folding process by Hsp90 inhibition leads to degradation of these client proteins. Because Hsp90 client proteins are so important in processes critical to the growth and survival of cancer cells (e.g., signal transduction and in transcription), Hsp90 inhibitors may serve as effective chemotherapeutic agents against a number of cancers. This hypothesis has been clinically validated by the geldanamycin analogs 17- AAG, and 17-DMAG. However, these ansamycin analogs suffer from poor pharmacokinetic properties and off- target toxicity. Thus, there is a need for improved Hsp90 inhibitors. This Phase I proposal focuses on synthesis, biological assessment and crystallography of four novel series of Hsp90 inhibitors that were designed using Locus' innovative computational technology. The ultimate proposed product of this research is an orally administered cancer therapeutic drug targeting Hsp90.

描述（由申请人提供）：尽管最近在癌症治疗方面取得了进展，但新型抗癌治疗剂的鉴定仍然是迫切需要的。热休克蛋白 90 (Hsp90) 是一种分子伴侣，可结合并折叠多种客户蛋白，包括许多关键的癌症相关靶标，例如激酶 Bcr-Abl、Raf-1 和 SRC 家族激酶（例如 SRC、LCK 和 FYN）、突变的 p53、ErbB2 和类固醇激素受体。 Hsp90 抑制对折叠过程的破坏导致这些客户蛋白的降解。由于 Hsp90 客户蛋白在癌细胞生长和存活的关键过程（例如信号转导和转录）中非常重要，因此 Hsp90 抑制剂可以作为针对多种癌症的有效化疗剂。这一假设已通过格尔德霉素类似物 17-AAG 和 17-DMAG 得到临床验证。然而，这些安沙霉素类似物具有较差的药代动力学特性和脱靶毒性。因此，需要改进的Hsp90抑制剂。该第一阶段提案重点关注四个新型 Hsp90 抑制剂系列的合成、生物学评估和晶体学，这些抑制剂是使用 Locus 的创新计算技术设计的。这项研究的最终提议产品是一种针对 Hsp90 的口服癌症治疗药物。